Wafer and capsule formulations with enhanced dissolution rates for fenofibrate

ABSTRACT

The invention relates to developing a novel water and capsule formulation using fenofibrate which is difficult to dissolve and control its release rate in vitro. For example, the invention relates to the creation of capsules and wafers comprising: fenofibrate, a surfactant, a carrier wax, a film former, a plasticizer, and optionally a super disintegrant or other ingredients. The invention further relates to the process of forming such capsules and wafers.

INCORPORATION BY REFERENCE

The present application claims priority from PCT Patent Application No.PCT/IB2012/003123 filed on Dec. 14, 2012, which claims priority fromU.S. Provisional Patent Application No. 61/570,381 filed on Dec. 14,2011, the disclosures of which are incorporated herein by reference intheir entirety. Any foregoing applications and all documents citedtherein or during their prosecution (“application cited documents”) andall documents cited or referenced in the application cited documents,and all documents cited or referenced herein (“herein cited documents”),and all documents cited or referenced in herein cited documents,together with any manufacturer's instructions, descriptions, productspecifications, and product sheets for any products mentioned herein orin any document incorporated by reference herein, are herebyincorporated herein by reference, and may be employed in the practice ofthe invention.

FIELD OF THE INVENTION

It is noted that citation or identification of any document in thisapplication is not an admission that such document is available as priorart to the present invention.

The U.S. Food and Drug Administration's Biopharmaceutics ClassificationSystem (BCS) provides guidance for predicting the gastro-intestinal drugabsorption. The drugs are classified in BCS based on the parameters ofsolubility and permeability. Cook et al., AAPS J., 2008; 10(2): 206-310.

The BCS class boundaries are:

1. Solubility boundaries—It is based on the highest dose strength of animmediate release product. A drug is considered highly soluble when thehighest dose strength is soluble in 250 mL or less of aqueous media overthe pH range of 1 to 7.5. The volume estimate of 250 mL is derived fromtypical bioequivalence study protocols that prescribe administration ofa drug product to fasting human volunteers with a glass of water.

Moreover, compounds can also be characterized by their dissolution rateswherein a rapidly dissolving compound is a compound where no less than85% of the labeled amount of the drug substance dissolve within 30minutes using USP Dissolution Apparatus 1 at 100 RPM or Apparatus 2 at50 RPM in a volume of 900 ml or less in following media: 0.1 N HCl orsimulated gastric fluid or pH 4.5 buffer and pH 6.8 buffer or simulatedintestinal fluid.

2. Permeability boundaries—It is based indirectly on the extent ofabsorption of a drug substance in humans and directly on the measurementof rates of mass transfer across human intestinal membrane.Alternatively non-human systems capable of prediction the drugabsorption systems capable of predicting the drug absorption in humanscan be used such as in-vitro culture methods). A drug substance isconsidered highly permeable when the extent of absorption in humans isdetermined to be 90% or more of the administered dose based on amass-balance determination or in comparison to an intravenous dose.

BCS Class II compounds are drug substances with high permeability andlow solubility. Examples of this category are glibenclamide/glyburide(antidiabetic), fenofibrate (an antilipemic), griseofulvin (antifungal)and lamotrigine (anticonvulsant). The bioavailability of these compoundsis limited by their solubility (solvation rate). An in vitro and in vivocorrelation can be found between the drug's solubility and itsbioavailability.

Unfortunately, the in-vitro release rates of the class II activepharmaceutical compounds according to the BCS definition are such thatthese types of compounds are only very slightly water soluble which isproblematic for delivering a drug for in vivo use by a patient in needof the pharmaceutical compound. Hence, the absorption of a poorlywater-soluble compound from orally administered solid dosage form iscontrolled by its dissolution rate in the gastrointestinal fluid presentat the absorption site.

One solution to the problem of low aqueous solubility of class IIpharmaceuticals is the use of liquisolid systems to form tablets andcapsules whereby a non-aqueous active drug solution or non-polar liquidactive drug is combined with a suitable carrier material to form wetparticles which are then combined with a coating material to form aliquisolid system. The liquisolid system is then further processed toform tablets and capsules. See for example, U.S. Pat. No. 6,096,337 andYadav et al., “Enhancement of Solubility and Dissolution Rate of BCSClass II Pharmaceuticals by Nonaquious Granulation Technique”, Int. J.Pharma. Res. Dev., vol. 1, issue 12, pages 1-12, February 2008 (ISSN:0974-9446).

However, the formation of liquisolid systems places special requirementson the components used such as simultaneously requiring good flow andgood compression properties when forming the liquisolid system. Inaddition, any excipient used must possess large surface areas and fineparticle sizes while not affecting the good flow and good compressionachieved by the other components of the liquisolid system.

-   -   Another solution is the use of polyethylene oxide (PEO) in        combination with griseofulvin to form the so called “solid        solution”. The solid solution is formed by mixing the active        drug with PEOs and then granulated and subsequently compressed        into tablets.    -   However, the formation of solid solution needs energy intensive        mixing using AMF-type mixers and the particle size of the        granulation cannot easily be controlled.    -   As such, there still exists a need in the art to produce a        dosage form which allows for the administration of BCS Class II        active compounds, such as fenofibrate, which are user friendly,        easy to administer and also produce a desirable pharmaceutical        effect despite their low solubility in aqueous media.

It is noted that in this disclosure and particularly in the claimsand/or paragraphs, terms such as “comprises”, “comprised”, “comprising”and the like can have the meaning attributed to it in U.S. Patent law;e.g., they can mean “includes”, “included”, “including”, and the like;and that terms such as “consisting essentially of” and “consistsessentially of” have the meaning ascribed to them in U.S. Patent law,e.g., they allow for elements not explicitly recited, but excludeelements that are found in the prior art or that affect a basic or novelcharacteristic of the invention.

It is further noted that the invention does not intend to encompasswithin the scope of the invention any previously disclosed product,process of making the product or method of using the product, whichmeets the written description and enablement requirements of the USPTO(35 U.S.C. 112, first paragraph) or the EPO (Article 83 of the EPC),such that applicant(s) reserve the right to disclaim, and herebydisclose a disclaimer of any previously described product, method ofmaking the product, or process of using the product.

SUMMARY OF THE INVENTION

The objective of this invention is to develop a novel wafer and capsuleformulation using fenofibrate which is difficult to dissolve and controlits release rate in vitro. Since an in vitro and in vivo correlation canbe found for this class of compounds, therefore it is highly desirableto design a formulation with controllable in vitro release rate.

These and other embodiments are disclosed or are apparent from andencompassed by the following Detailed Description.

BRIEF DESCRIPTION OF THE DRAWINGS

The following detailed description, given by way of example, but notintended to limit the invention solely to the specific embodimentsdescribed, may best be understood in conjunction with the accompanyingdrawings, in which:

FIG. 1 depicts the wafer dissolution rate of Examples 1 and 2.

FIG. 2 depicts the wafer dissolution rate of Examples 3 and 4.

FIG. 3 depicts the control of release rate by adjusting Cremophor RH 40concentration

FIG. 4 depicts the capsule formulation dissolution rate without superdisintegrants for Example 2 (low dose and high dose capsules)

FIG. 5 depicts the capsule formulation dissolution rate without superdisintegrants for Example 3 (low dose and high dose capsules)

FIG. 6 depicts the capsule formulation dissolution rate without superdisintegrants for Example 4 (low dose and high dose capsules)

FIG. 7 depicts the capsule formulation dissolution rate with superdisintegrants

FIG. 8 depicts the comparison of various low dose dissolution rates(top—Abbott Laboratories low dose Trilipix (fenofibrate); middle—TevaPharmaceuticals low dose Lofibra® (fenofibrate); bottom—LTS Lohmann lowdose fenofibrate (10% Chitopharm M, disclosed in Table 3) notcommercially available

FIG. 9 depicts the comparison of various high dose dissolution rates(top—Abbott Laboratories high dose Trilipix (fenofibrate); middle—TevaPharmaceuticals high dose Lofibra® (fenofibrate); bottom—LTS Lohmannhigh dose fenofibrate (10% Chitopharm M, disclosed in Table 4) notcommercially available

DETAILED DESCRIPTION OF EMBODIMENTS

It is to be understood that the figures and descriptions of the presentinvention have been simplified to illustrate elements that are relevantfor a clear understanding of the present invention, while eliminating,for purposes of clarity, many other elements which are conventional inthis art. Those of ordinary skill in the art will recognize that otherelements are desirable for implementing the present invention. However,because such elements are well known in the art, and because they do notfacilitate a better understanding of the present invention, a discussionof such elements is not provided herein.

The present invention will now be described in detail on the basis ofexemplary embodiments.

It has been found that wafer or capsule dosage forms can be formed whichallow for the administration of Class II active compounds with acontrolled release rate and/or enhanced dissolution which produces thedesired pharmaceutical effect despite their low solubility in aqueousmedia.

For the purposes of this invention the term strips, thin film and wafersare considered to be interchangeable.

One aspect of the invention is a wafer which comprises of fenofibrate,surfactant, carrier wax, film former, plasticizer and optionallyadditional ingredients.

In one embodiment of the invention, the wafer comprises of:

-   -   (a) 10 to 50% w/w of fenofibrate;    -   (b) 10 to 50% w/w of surfactant;    -   (c) 1 to 30% w/w of carrier wax;    -   (d) 10 to 60% w/w of film former; and    -   (e) 1 to 10% w/w of plasticizer.    -   In another embodiment of the invention, the wafer comprises of:    -   (a) 20 to 40% w/w of fenofibrate;    -   (b) 15 to 45% w/w of surfactant;    -   (c) 2 to 20% w/w of carrier wax;    -   (d) 20 to 50% w/w of film former; and    -   (e) 2 to 8% w/w of plasticizer.    -   In another embodiment of the invention, the wafer comprises of:    -   (a) 25 to 35% w/w of fenofibrate;    -   (b) 20 to 30% w/w of surfactant;    -   (c) 4 to 10% w/w of carrier wax;    -   (d) 30 to 40% w/w of film former; and    -   (e) 3 to 6% w/w of plasticizer.

In another embodiment of this aspect of the invention, the aboveembodiments do not contain any super distintegrant.

In another embodiment of the invention, the wafer additionally containsan amount of super disintegrant in a range selected from the groupconsisting of 2 to 40% w/w; 25 to 35% w/w; 10 to 20% w/w and 2 to 10%w/w.

Another aspect of the invention is a capsule which encapsulates acomposition which of fenofibrate, surfactant, carrier wax, film former,plasticizer, super disintegrant and optionally additional ingredients.

In one embodiment of the invention, the composition encapsulated by thecapsule comprises of:

-   -   (a) 10 to 50% w/w of fenofibrate;    -   (b) 10 to 50% w/w of surfactant;    -   (c) 1 to 30% w/w of carrier wax;    -   (d) 2 to 40% w/w of film former;    -   (e) 1 to 10% w/w of plasticizer; and    -   (f) 2 to 40% w/w of super disintegrant.

In another embodiment of the invention, the composition encapsulated bythe capsule comprises of:

-   -   (a) 20 to 40% w/w of fenofibrate;    -   (b) 15 to 45% w/w of surfactant;    -   (c) 2 to 20% w/w of carrier wax;    -   (d) 15 to 35% w/w of film former;    -   (e) 2 to 8% w/w of plasticizer; and    -   (f) 10 to 20% w/w of super disintegrant.

In another embodiment of the invention, the composition encapsulated bythe capsule comprises of:

-   -   (a) 25 to 35% w/w of fenofibrate;    -   (b) 20 to 30% w/w of surfactant;    -   (c) 4 to 10% w/w of carrier wax;    -   (d) 15 to 35% w/w of film former;    -   (e) 3 to 6% w/w of plasticizer; and    -   (f) 10 to 20% w/w of super disintegrant.

In another embodiment of the invention, when the amount of film formeris 2 to 10% w/w, the amount of super disintegrant is 25 to 35% w/w. Inanother embodiment of the invention, when the amount of film former is15 to 25% w/w, the amount of super disintegrant is 10 to 20% w/w. Inanother embodiment of the invention, when the amount of film former is25 to 35% w/w, the amount of super disintegrant is 2 to 10% w/w.

In another embodiment of the invention, the composition encapsulated bythe capsule is in the form of fine particles with size ranges selectedfrom the group of of 40 μm-400 μm, 40 μm-200 μm, 50 μm-100 μm, 5 μm-100μm, 5 μm-50 μm, and 10 μm-25 μm in diameter.

In another embodiment of this invention, the fenofibrate has asolubility in water (at room temperature (20-25° C.) and physiologicalpH) selected from the ranges of less than 0.20 mg/mL; less than 0.10mg/mL; and less than 0.05 mg/mL.

In another embodiment of the invention, the wafer or capsule has aresidual moisture selected from the ranges of less than 10% by weight,less than 5% by weight; and less than 1% by weight (all weights based onthe total weight of the wafer or capsule).

In one embodiment of the invention, the surfactants include, but are notlimited to those surfactants used in mucoadhesive films such as thosedescribed in U.S. Pat. Nos. 5,948,430; 6,284,264; 6,592,887 and6,709,671 (assigned to LTS LohmannTherapie-Systeme AG) and may be one ormore cationic surfactants, anionic surfactants, nonionic surfactants.Combination of surfactants can include embodiments wherein the firstcomponent may be a polyoxyethylene sorbitan fatty acid ester or aα-hydro-Ω-hydroxypoly (oxyethylene)poly(oxypropylene)poly(oxyethylene)block copolymer, while the second component may be a polyoxyethylenealkyl ether or a polyoxyethylene castor oil derivative. One embodimentof the surfactant is that the HLB value of the polyoxyethylene sorbitanfatty acid ester is between 10 and 20, e.g. a range of 13 to 17. Theα-hydro-Ω-hydroxypoly (oxyethylene)poly(oxypropylene)poly(oxyethylene)block copolymer can contain at least 35 oxypropylene-units, e.g. notless than 50 oxypropylene-units.

Alternatively, other surfactants, include, but are not limited to,lecithin, cetyl alcohol, sodium lauryl sulfate, the Spans™ and Tweens™which are commercially available from ICI Americas, Inc. Ethoxylatedoils, including ethoxylated castor oils, such as Cremophor® which iscommercially available from BASF, are also useful. Carbowax™ is yetanother modifier which is very useful in the present invention. Tween™.or combinations of surface active agents may be used to achieve thedesired hydrophilic-lipophilic balance (“HLB”). The present invention,however, does not require the use of a surfactant and films orfilm-forming compositions of the present invention may be essentiallyfree of a surfactant while still providing the desirable uniformityfeatures of the present invention.

In one embodiment of the invention, the surfactants are selected fromthe group consisting of PEG 8000, PEG 400, mono-, di- and tri-glyceridesof behenic acid, polyoxyl 40 hydrogenated castor oil, polyoxyethylene(80) sorbitan monooleate and mixtures thereof.

In one embodiment of this aspect of the invention, the carrier waxmaterial includes, but is not limited to animal waxes, vegetable waxes,mineral waxes, petroleum waxes and synthetic waxes.

Animal waxes include but are not limited to beeswax, spermaceti (mainconstituent cetyl palmitate) and lanolin. Vegetable waxes include butare not limited to carnuba wax, candelilla wax, ouricury wax, sugarcanewax, retamo wax, jojoba oil, and epicuticular waxes. Petroleum waxesinclude paraffins, microcrystalline wax, petroleum jelly, montan wax andmixtures of saturated alkanes. Synthetic waxes include but are notlimited to waxes from the cracking of polyethylenes, Fischer-Tropschwaxes, substituted amide waxes and polymerized α-olefins.

In one embodiment of the invention, the carrier wax is sorbitanstearate.

In one embodiment of this aspect of the invention, the film formingpolymers include, but are not limited to cellulose and cellulosederivatives, such as, methyl cellulose, ethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,carboxymethyl cellulose, sodium carboxymethyl cellulose, synthetic ornatural gums, such as, xanthan gum, tragacanth gum, guar gum, acaciagum, arabic gum, locust bean gum, methacrylic acid polymers, methacrylicacid copolymers, acrylic acid polymers, acrylic acid copolymers,polyacrylamides, polyalkylene oxides, polyalkylene glycols, pullulan,bean starches, pea starches, polyvinyl pyrrolidone, polyvinyl alcohol,carrageenan, alginic acid, salts of alginic acid, carboxyvinyl polymers,pectin, pectin derivatives, xanthan gum, xanthan gum derivatives, starchand starch derivatives and mixtures thereof.

In another embodiment of the invention, the film forming polymer ishydroxypropylmethyl cellulose, methyl cellulose, sodiumcarboxymethylcellulose, sodium alginate and mixtures thereof.

In one embodiment of the invention, the plasticizers include, but arenot limited to adipates, benzoates, 1,2-propanediol and/or 1,3- and/or1,4-butanediol and/or polypropylene glycol polyesters with adipic acid,acetic acid or C₁₀-C₁₈ fatty acids or n-octanol and/or n-decanol,trimellitates, phosphates, sebacates, alkyl sulphonates, epoxidizedlinseed and soybean oils, DINCH® and/or citrates, alkylene glycols,polyalkylene glycols, glycerol (glycerin), triacetin, deacetylatedmonoglyceride, polyethylene glycols, diethyl salate, triethyl citrateand mixtures thereof.

The term “super disintegrants” is a term of art which refers to thesubstances which can be used as disintegrants at lower levels thanstarch, a widely used disintegrant in tablets. Augsburger et al., “SuperDisintegrants: Characterization and Function” from Encyclopedia ofPharmaceutical Technology, Third Edition, Volume 6, ed. by JamesSwarbrick, pages 3553-3567 (2008). Examples of superdisintegrantsinclude, but are not limited to modified starches such as sodiumcarboxymethyl starch, sodium starch glycolate; cross-linkedpolyvinylpyrrolidones such as crospovidone; modified celluloses such asinternally cross-linked sodium carboxymethylcellulose, e.g.croscarmellose; and chitosans of various molecular weights.

In another embodiment of the invention, the super disintegrant ischitosan.

In another embodiment of the invention, the average molecular weightrange of chitosan is selected from the ranges consisting of from 25 kDto 10,000 kD, 500 kD to 5,000 kD, 100 kD to 2,000 kD and 50 kD to 1,000kD. (Weight-average molecular weight as determined by gel permeationchromatography (GPC)/size exclusion chromatography (SEC))

In another embodiment of this aspect of the invention, the wafers andcapsules of the invention may optionally contain one or more additionalingredients which include, but are not limited to disintegrants, tastemasking agents, flavoring agents, sweeteners, coloring agents,antioxidants, chelating agents, antimicrobial agents, preservatives,mucoadhesives, permeation enhancers and mixtures thereof.

These optional ingredients can be present in an amount from 0 to 10%w/w. In another embodiment of the invention the amount of optionalingredients is 0.1 to 2% w/w. In another embodiment of the invention theamount of optional ingredients is 0.5 to 5% w/w.

In one embodiment of this aspect of the invention, the wafers andcapsules further comprise disintegrants which include, but are notlimited to bentonite, pectin, silica gel, carbopol, carrageenan, sodiumalginate, xanthan gum, gellum gum, guar gum, Aratex hydoxy propylstarch, corn starch, gum Arabic, locust bean gum, tragacanth, PEG withvarious molecular weights, anionic and cationic ion exchange resins andmaltodextrin.

In another embodiment of the invention, the wafers and capsules furthercomprise an active ingredient used in the film can be coated to mask thetaste of the active ingredient or to prevent the active ingredient fromnumbing the tongue or other surfaces in the oral cavity. The coatingsthat can be used are known to those skilled in the art. These includepolymers such, as Eudragit® E, cellulosics, such as ethylcellulose, andthe like.

An additional way to mask the taste of the active ingredient is by usingan ion exchange resin such as Amberlite IRP-69, available from Rohm andHaas, and Dow XYS-40010.00, available from the Dow Chemcial Co. or byother means known in the art, e.g. U.S. Pat. No. 7,615,235 describesforming film-shaped or wafer-shaped pharmaceutical preparations whichcontain at least one active substance and at least one gas-formingcomponent (e.g. a carbon dioxide forming substance) to mask taste.

U.S. Pat. No. 5,593,684 describes the use of terpene-containing plantsecretions as “etherial oils” in lozenges for oral application in orderto mask the unpleasant taste of nicotine.

In another embodiment of the invention, the wafers and capsules furthercomprise flavoring agents which include, but are not limited toessential oils or extracts of menthol, wintergreen, peppermint, sweetmint, spearmint, vanillin, cherry, butterscotch, chocolate, cinnamon,clove, lemon, orange, raspberry, rose, spice, violet, herbal, fruit,strawberry, grape, pineapple, vanilla, peppermint, peach, kiwi, papaya,mango, coconut, apple, coffee, plum, watermelon, nuts, green tea,grapefruit, banana, butter, and chamomile.

In another embodiment of the invention, the wafers and capsules furthercomprise sweeteners which include, but are not limited to dextrose,lactose, fructose, mannitol, sucrose, trehalose, sucralose, xylitol,mannitol, aspartame, saccharin, sorbitol, sodium saccharin, sodiumcyclamate, acesulfame, honey, isomalt, maltodextrin, dextrin, dextratesand mixtures thereof.

In another embodiment of the invention, the wafers and capsules furthercomprise coloring agents which include, but are not limited to ediblepigments, dyes, natural food colors, and synthetic colorants such asFD&C coloring agents and mixtures thereof.

In another embodiment of the invention, the wafers and capsules furthercomprise antioxidants which include, but are not limited to chelatingagents, sodium bisulfite, sodium metabisulfite, ascorbic acid, ascorbylpalmitate.

In another embodiment of the invention, the wafers and capsules furthercomprise chelating agents which include, but are not limited to EDTA andEGTA.

In another embodiment of the invention, the wafers and capsules furthercomprise antimicrobial agents and preservatives which include, but arenot limited to butylated hydroxyanisol, butylated hydroxyltoluene,parabens, parebens derivatives, sorbic acids and derivatives, benzoicacid and derivatives, propionic acid and derivatives, acetic acid andderivatives and mixtures thereof.

In another embodiment of the invention, the wafers and capsules furthercomprise mucoadhesives which include, but are not limited to ediblesilicone, polyacrylic acids, Carbopols®, etc.

In another embodiment of the invention, the permeation enhancersinclude, but are not limited to non-ionic surfactants, such aspoloxamer, Brij®, Span®, Myrj®, Tween®, bile salts, sodiumglycodeoxycholate, sodium glycocholate, sodium taurodeoxycholate, sodiumtaurocholate, Ozone®, fatty acids, such as oleic and caprylic acidderivatives, cyclodextrins, such as α-, β-, γ-cyclodextrin, methylatedβ-cyclodextrins, chelators, such as EDTA, sodium citrate andpolyacrylates; and cationic amino acids, such as poly-L-arginine,L-lysine.

Other excipients and pharmaceutically acceptable agents can also beadded such as those described in Remington—The Science and Practice ofPharmacy, 21^(st) Edition (2005), Goodman & Gilman's The PharmacologicalBasis of Therapeutics, 11^(th) Edition (2005) and Ansel's ParmaceuticalDosage Forms and Drug Delivery Systems (8^(th) Edition), edited by Allenet al., Lippincott Williams & Wilkins, (2005).

Another aspect of the invention is directed toward the process of makinga wafer with a dosage of a fenofibrate which comprises:

-   -   (a) forming a hot melt with a fenofibrate, an emulsifier and a        carrier wax material;    -   (b) homogenizing the hot melt and adding the hot melt to an        aqueous solution to form an oil-in-water (O/W) emulsion with        microparticles of the BCS class II compound;    -   (c) cooling the O/W emulsion and adding a film forming polymer        and optionally, a super disintegrant, to form a liquid mass; and    -   (d) drying the liquid mass to form a film; and    -   (e) cutting the film to form the wafer.

Another aspect of the invention is directed toward the process of makinga capsule with a dosage of fenofibrate which comprises:

-   -   (a) forming a hot melt with fenofibrate, an emulsifier and a        carrier wax material;    -   (b) homogenizing the hot melt and adding the hot melt to an        aqueous solution to form an oil-in-water (O/W) emulsion with        microparticles of fenofibrate;    -   (c) cooling the O/W emulsion and adding a film forming polymer        and optionally, a super disintegrant, to form a liquid mass; and    -   (d) drying the liquid mass to form a film;    -   (e) cutting the film to form the wafer;    -   (f) forming the fine particles from the wafer;    -   (g) mixing the fine particles with a super disintegrant to form        a particle mixture; and    -   (h) loading the particle mixture into a capsule.

In another embodiment of the invention, the forming of the fineparticles can be accomplished by using a razor to produce particles witha size ranges of 40 μm-400 μm, 40 μm-200 μm, and 50 μm-100 μm indiameter.

In another embodiment of the invention, the forming of the fineparticles can be accomplished by freeze milling to produce particleswith a size ranges of 5 μm-100 μm, 5 μm-50 μm, and 10 μm-25 μm indiameter.

Another aspect of the invention is a method of lowering cholesteroland/or triglyceride levels to by administering to a patient in needthereof the wafer or capsule of the invention.

In one embodiment of the invention, the administration is via oral,buccal, sublingual, or transmucosal administration.

In another embodiment of the invention, the active agent is released ata rate selected from the rates consisting of at least 75% by weightwithin 60 minutes of administration; at least 85% within 60 minutes ofadministration; and at least 90% within 60 minutes of administration (%by weight based on the total weight of the active present).

In another embodiment of the invention, the active agent is released ata rate selected from the rates consisting of at least 75% by weightwithin 45 minutes of administration; at least 85% within 45 minutes ofadministration; and at least 90% within 45 minutes of administration (%by weight based on the total weight of the active present).

In another embodiment of the invention, the active agent is released ata rate selected from the rates consisting of at least 75% by weightwithin 30 minutes of administration; at least 85% within 30 minutes ofadministration; and at least 90% within 30 minutes of administration (%by weight based on the total weight of the active present).

The invention is further described by the following non-limitingexamples which further illustrate the invention, and are not intended,nor should they be interpreted to, limit the scope of the invention.

OPERATIVE EXAMPLES

The Subject Matter of the Present Invention is Elucidated in More DetailBelow, Using Examples, without any Intention that the Subject Matter ofthe Invention Should be Confined to these Exemplary Embodiments.Formation of Wafers and Capsules

I. Hot Melt Formation

Fenofibrate

Compitrol® 888 (mono-, di- and triglycerides of behenic acid)

Sorbitan Stearate

Cremophor® RH40 (polyoxyl 40 hydrogenated castor oil)

Fenofibrate is heated together with Compitrol® 888, sorbitan stearateand Cremphor® RH40 in a small beaker up to 100° C. until dissolved. Thehot melt mixture is stirred with a spatula until uniform if necessary.

II. Formation of Emulsion with Micropartides of Fenofibrate

Hot melt mixture

Purified water

Polysorbate 80 (polyoxyethylene (80) sorbitan monooleate)

Purified water and polysorbate 80 is heated to 100° C. on a hot plate.Homogenize and stir the mixture at 21,500 rpm (adjust speed to avoidsplashing). Gradually add the hot melt and continue the homogenizationto form an oil-in-water (O/W) emulsion with microparticles offenofibrate. While homogenizing, remove hot plate (heat). Stophomogenization and mix at 1,000 rpm. Add crushed ice cubes at the rateof one teaspoon per second and record final temperature of the emulsionwith microparticles of fenofibrate. Use ice bath to maintain temperatureat 15° C.

III. Formation of Wafers

Emulsion with Microparticles of Fenofibrate

Sodium CMC (Carboxymethylcellulose)

Chitopharm® M (Chitosan)—optional

Cremophor® RH 40

Glycerin

To the emulsion with microparticles of fenofibrate, while mixing at 400rpm, add sodium CMC (Cekol® 30P) and optionally, gradually add chitosan(Chitopharm® M). Increase mixing speed to 800 rpm for 60 minutes. AddCremphor® RH 40 and glycerin and continue mixing at 800 rpm for 15minutes to form a liquid mass.

Cast the liquid mass onto an intermediate liner (process liner) using a1000 μm wet gap, with the manual coater available in the laboratory. Theliquid mass was oven dried at 35° C. for 15-20 minutes, resulting in adry film.

Wafers were cut into defined sizes out of the resulting dry film with asuitable die-cutter. The cut wafers were then separated from the filmand inserted into prefabricated pouches.

Examples Of Wafers

TABLE 1 (without super disintegrant) % w/w Compound Ex. 1 Ex. 2 Ex. 3Ex. 4 Ex. 5 Fenofibrate 35.0 27.8 33.0 30.0 30.0 PEG 8000 22.0 PEG 4003.0 Compitrol ® 888 18.5 12.0 10.0 10.0 Polysorbate ® 80 2.8 3.0 5.0 5.0Cremophor ® RH40 4.6 7.0 10.0 11.0 Sorbitan stearate (wax) 9.3 5.0 5.06.0 Metolose ® 60SH50 5.0 4.6 5.0 5.0 5.0 (hydroxypropylmethylcellulose/methylcellulose) Pharmacoat ® 603 29.0(hydroxypropylmethylcellulose) Cekol ® 30P (sodium 27.6 30.0 30.0 30.0carboxymethylcellulose) Glycerin 6.0 4.6 5.0 5.0 3.0

TABLE 2 (with super disintegrant) % w/w Compound Ex. 6 Ex. 7 Ex. 8 Ex. 9Ex. 10 Ex. 11 Fenofibrate 30.0 30.0 30.0 30.0 30.0 30.0 Compitrol ® 88810.0 10.0 10.0 10.0 10.0 10.0 Polysorbate ® 80 5.0 5.0 5.0 5.0 5.0 5.0Cremophor ®RH40 10.0 10.0 10.0 10.0 10.0 10.0 Sorbitan stearate (wax)5.0 5.0 5.0 5.0 5.0 5.0 Metolose ® 60SH50 5.0 (hydroxypropylmethylcellulose/methylcellulose) Cekol ® 30P (sodium 20.0 20.0 30.0carboxymethylcellulose) Manucol ® LD (sodium alginate) 30.0 20.0Glycerin 5.0 5.0 5.0 5.0 5.0 5.0 Sodium starch glycolate 30.0 15.0Chitopharm ® M (milled or 15.0 15.0 non-milled) Chitopharm ® M (milled)5.0 5.0

The wafer dissolution rate are shown in FIG. 1 (for example 2) and FIG.2 (for examples 3 and 4). The release rate of fenofibrate was controlledby adjusting Cremophor® RH 40 concentration and is depicted in FIG. 3which shows a linear relationship between the amount of surfactant andthe % release of fenofibrate.

IV. Formation of Capsules

The wafers were cut using a doctor's knife or razor to a particle sizebetween 40 μm-400 μm in width. The particles were filled into 150 mg and450 mg capsules, corresponding to fenofibrate content approximately 50mg (low dose) and 150 mg (high dose), respectively. The capsules werethen subjected to USP dissolution using triplicate samples.

V. Capsule Dissolution Rate Without Super Disintegrants

The capsule dissolution rates without super disintegrants are shown inFIGS. 4, 5 and 6. As can be seen from these figures, the % w/w offenofibrate released is linear with respect to time.

IV. Capsule Dissolution Rate with Super Disintegrants

The capsule dissolution rate with super disintegrants(Chitopharm®—Chitosan) are shown in FIG. 7. As can be seen from FIG. 7,the % w/w of fenofibrate released is hyperbolic with respect to time.60% of fenofibrate release was achieved at 20 minuts for 6.3% chitosanand 70% of fenofibrate release was achieved for 10% chitosan.

VII. Comparative Screening Studies (Super Disintegrant Screening vs.Disintegrants)

Super disintegrants, such as, croscarmellose (crosslinked sodiumcarboxymethylcellulose), sodium starch glycolate, crospovidone(polyvinylpyrrolidone), in addition to Chitopharm® L, M and S (chitosan)were studied using a dissolution screening method and compared againstthe use of disintegrants such as effervescent technology, bentonite,pectin, Carbopol® (polymers of acrylic acid cross-linked withpolyalkenyl ethers or divinyl glycol), carrageenan, sodium alginate,xanthum gum, gellum gum, tragacanth. The same dissolution bath,dissolution media and sinker were used. The dissolution time of capsuleswere observed.

Super Disintegrant and Disintegrant Screening Results

TABLE 3 Various Polymers for Low Dose Fenofibrate (167 mg capsuleWeight) Formulation 10 20 30 40 50 (Ex. #) Polymer Added mm min min minmin Comments 5 Kollidon CL 3%  0% 20% 40% 60% 100% Particle Floating 5Croscarmellose 5%  0% 25% 40% 50%  60% 70% out at 60 min 5 Bentonite 5% 0%  0% 10% 30%  70% 100% out at 60 min 5 Bentonite 5% and  5% 10% 25%35%  45% 100% out at 60 min Crospovidone 5% 5 2.5% pectin and  0% 15%20% 50% 100% Particle Floating 2.5% Silica gel 5 Carbopol 971 5%  5% 10%15% 25%  50% 60% out at 60 min 5 Carrageenan 5%  0% 20% 50% 60%  75%100% out at 60 min 5 Sodium alginate 5%  5% 10% 15% 20%  40% 60% at 60min 5 Xanthan gum 5% 10% 15% 20% 25%  60% 100% out at 60 min 5 Gellumgum 5%  5% 10% 15% 20%  95% 100% out at 60 min 5 Tragacanth 5%  0%  0%40% 50%  60% 70% out at 60 min 5 Chitopharm ® L 10% 50% 80% 100%  100% 100% 100% out at 30 min 5 Chitopharm ® M 10% 30% 95% 100%  100%  100%95% out at 20 min 5 Chitopharm ® S 10% 40% 95% 100%  100%  100% 95% outat 20 min 5 Chitopharm ® M 7% and 50% 70% 100%  100%  100% 100% out at26 min Kollidon ® CL 3% 7 Chitopharm ® M 10% 40% 60% 65% 100%  100% 100%out at 40 mm 7 Kollidon ® CL 10% 10% 50% 60% 100%  100% 100% out at 40mm 8 Chitopharm ® M 10% 75% 95% 100%  100%  100% 100% out at 25 min 8Kollidon ® CL 10% 10% 30% 50% 90% 100% 100% out at 47 min 9 Chitopharm M10% 40% 80% 100%  100%  100% 100% out at 27 min 9 Kollidon ® CL 10% 25%50% 60% 70% 100% 100% out at 45 min 10 (Manucol LD & milled 80% 98% 99%100%  100% 100% out at 33 min Chitopharm ® M embedded) Chitopharm ® M10% 10 (Manucol LD & milled 20% 40% 50% 80%  98% 100% out at 66 minChitopharm ® M embedded) Kollidon ® CL 10% 11 (Manucol LD & Chitopharm ®M 50% 70% 100%  100%  100% 100% out at 23 min embedded) Chitopharm ® M10% 11 (Manucol LD & Chitopharm ® M  0% 35% 80% 100%  100% 100% out at36 min embedded) Kollidon ® CL 10%

TABLE 4 Various Polymers for High Dose Fenofibrate (500-550 mg CapsuleWeight) Formulation 10 20 30 40 50 (Ex. #) Polymer Added min min min minmin Comments 5 Chitopharm ® L 10% 10%  20% 30% 50% 100%  100% out at 49min 5 Chitopharm ® M 10% 15%  25% 40% 60% 100%  100% out at 47 mm 5Chitopharm ® S 10% 15%  30% 50% 70% 80% 100% out at 62 min 5Chitopharm ® M 7% & 20%  40% 60% 80% 85% 90% out at 60 min Kollidon ® CL3% 5 C-Aratex Hydroxypropyl 0% 10% 15% 20% 25% 30% out ay 60 min Starch10% 5 Corn Starch 10% 0% 15% 20% 25% 30% 35% 0ut at 60 min 5 Gum Arabic10% 0%  5% 10% 15% 20% 30% out at 60 min 5 Locust Bean Gum 10% 5% 10%15% 20% 25% 30% out at 60 min 5 PEG8000 10% 0%  5% 10% 15% 20% 25% outat 60 min 5 Amberlite IRP64 10% 1%  5% 10% 15% 20% 25% out at 60 min 5Amberlite IRP69 10% 0%  1%  5% 10% 15% 20% out at 60 min 5 AmberliteIRP88 10% 0%  1%  5% 10% 15% 20% out at 60 min 5 Maltodextrin 10% 1%  2% 5% 10% 15% 20% out at 60 min 5 Kollidon ® CL 9.09%, 5% 10% 15% 20% 25%40% out at 60 min Tartaric Acid 4.55%, Ammonium Bicarbonate 4.55% 7Chitopharm ® M 10% 5% 10% 15% 20% 30% 50% out at 70 min 7 Kollidon ® CL10% 0%  5% 10% 15% 20% 30% out at 60 mm 8 Chitopharm ® M 10% 10%  20%35% 45% 50% 65% out at 60 min 8 Kollidon ® CL 10% 5% 10% 20% 30% 35% 40%0ut at 60 mm 9 Chitopharm ® M 10% 20%  30% 40% 45% 50% 60% out at 70 min9 Kollidon ® CL 10% 5% 10% 20% 30% 35% 45% 0ut at 70 min 10 Chitopharm ®M 10% 15%  35% 41% 60% 68% 100% out at 58 min 10 Kollidon ® CL 10% 10% 20% 25% 30% 35% 45% out at 70 mm 11 Chitopharm ® M 10% 20%  35% 50% 75%98% 90% our at 41 mm 11 Kollidon ® CL 10% 5% 10% 30% 50% 80% 85% out at60 min

Having thus described in detail various embodiments of the presentinvention, it is to be understood that the invention defined by theabove paragraphs is not to be limited to particular details set forth inthe above description as many apparent variations thereof are possiblewithout departing from the spirit or scope of the present invention.

While this invention has been described in conjunction with the specificembodiments outlined above, it is evident that many alternatives,modifications, and variations will be apparent to those skilled in theart. Accordingly, the preferred embodiments of the invention as setforth above are intended to be illustrative, not limiting. Variouschanges may be made without departing from the spirit and scope of theinventions as defined in the following claims.

The invention claimed is:
 1. A process of making a wafer with a dosageof a BCS class II compound which comprises: (a) forming a hot melt byheating together the BCS class II compound with an emulsifier and acarrier wax material; (b) homogenizing the hot melt and adding the hotmelt to an aqueous solution to form an oil-in-water (O/W) emulsioncomprising microparticles of the BCS class II compound; (c) cooling theO/W emulsion followed by adding a film forming polymer, and optionally asuper disintegrant, to the cooled O/W emulsion to form a liquid mass;(d) drying the liquid mass to form a film; and (e) cutting the film toform the wafer; wherein the BCS class II compound consists essentiallyof fenofibrate.
 2. A process of making a capsule with a dosage of a BCSclass II compound which comprises: (a) forming a hot melt by heatingtogether the BCS class II compound with an emulsifier and a carrier waxmaterial; (b) homogenizing the hot melt and adding the hot melt to anaqueous solution to form an oil-in-water (O/W) emulsion comprisingmicroparticles of the BCS class II compound; (c) cooling the O/Wemulsion followed by adding a film forming polymer, and optionally asuper disintegrant, to the cooled O/W emulsion to form a liquid mass;(d) drying the liquid mass to form a film; (e) cutting the film to forma wafer; (f) forming fine particles from the wafer; (g) mixing the fineparticles with a super disintegrant to form a particle mixture; and (h)loading the particle mixture into a capsule; wherein the BCS class IIcompound consists essentially of fenofibrate.
 3. The process of making awafer as claimed in claim 1, wherein: the carrier wax material isselected from the group consisting of one or more of animal waxes,vegetable waxes, mineral waxes, petroleum waxes, synthetic waxes,beeswax, spermaceti (main constituent cetyl palmitate), lanolin, camubawax, candelilla wax, ouricury wax, sugarcane wax, retamo wax, jojobaoil, epicuticular waxes, paraffins, microcrystalline wax, petroleumjelly, montan wax, mixtures of saturated alkanes, waxes from thecracking of polyethylenes, Fischer-Tropsch waxes, substituted amidewaxes, polymerized a-olefins and sorbitan stearate; the film formingpolymer is selected from the group consisting of one or more ofcellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethylcellulose, sodium carboxymethyl cellulose, synthetic or natural gums,xanthan gum, tragacanth gum, guar gum, acacia gum, arabic gum, locustbean gum, methacrylic acid polymers, methacrylic acid copolymers,acrylic acid polymers, acrylic acid copolymers, polyacrylamides,polyalkylene oxides, polyalkylene glycols, pullulan, bean starches, peastarches, polyvinyl pyrrolidone, polyvinyl alcohol, carrageenan, alginicacid, salts of alginic acid, carboxyvinyl polymers, pectin, xanthan gum,starch, and mixtures thereof; and the superdisintegrant is selected fromthe group consisting of one or more of sodium carboxymethyl starch,sodium starch glycolate; cross-linked polyvinylpyrrolidones,crospovidone; cross-linked sodium carboxymethylcellulose,croscarmellose; and chitosan.